Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH3:6][O:7][C:8]1[CH:33]=[CH:32][C:11]([CH2:12][NH:13][C:14]2[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]([NH:23][C:24]3[N:25]=[CH:26][C:27]([C:30]#[N:31])=[N:28][CH:29]=3)[CH:15]=2)=[CH:10][CH:9]=1>CCO>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][NH:13][C:14]2[C:19]([NH2:20])=[CH:18][N:17]=[C:16]([NH:23][C:24]3[N:25]=[CH:26][C:27]([C:30]#[N:31])=[N:28][CH:29]=3)[CH:15]=2)=[CH:32][CH:33]=1
Reactant: COc1ccc(CNc2cc(Nc3cnc(C#N)cn3)ncc2[N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(CNc2cc(Nc3cnc(C#N)cn3)ncc2N)cc1
Temperature: 70 °C
Yield: 84.7 %

Procedure:
Tin(II)chloride dihydrate (1.59 g, 7.04 mmol) was added portionwise to 5-(4-(4-methoxybenzylamino)-5-nitropyridin-2-ylamino)pyrazine-2-carbonitrile (531 mg, 1.41 mmol) in absolute EtOH (10 mL) at room temperature. The mixture was heated at 70° C. for 2 hours before being concentrated in vacuo. The residue was suspended in a mixture of ethyl acetate and saturated sodium bicarbonate solution, then filtered to remove insoluble material. The solids were then washed with EtOAc. The aqueous phase was re-extracted with ethyl acetate and the combined organic extracts were washed with brine, dried (Na2SO4) and concentrated to give crude title compound (415 mg) as a brown solid. The product was 50% pure by LCMS analysis and was used without further purification. LCMS (2) Rt=1.73 min; m/z (ESI−) 346 (M−H); (ESI+) 348 (MH+).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:12]=[CH:11][C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[C:14](#[N:16])[CH3:15].N[C@H](CO)C.C(OCC)(=O)C>N1C=CC=CC=1>[S:1]([N:16]1[CH2:15][CH2:14]1)([C:4]1[CH:12]=[CH:11][C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC#N
Agent: C[C@H](N)CO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CC2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 100 gallon glass-lined vessel, fitted with mechanical stirrer, addition funnel, nitrogen inlet and temperature probe, was charged with nosylchloride (52.7 kg) and acetonitrile (75L) at room temperature under nitrogen. The slurry was cooled to about 0° C. A solution of L-alaninol (7) (7.5 kg) in pyridine (32L) was added over about an hour maintaining the reaction temperature less than 10° C. during the addition, and then the mixture was aged for about two hours at about 3° C. to 5° C. Ethyl acetate (188L) and water (75L) were added and the phases were mixed. The lower aqueous layer was removed and the organic layer was washed with 1M citric acid (2×37.5L) and water (37.5L). The organic layer was cooled to about 15° C. and water (37.5L) was added. Hunig's base (N,N-diisopropylethylamine) (27L) was added for over 30 minutes. The two-phase mixture was aged at 20° C. for about an hour to complete the cyclization, and then the lower aqueous layer was removed and extracted with ethyl acetate (37.5L). The combined organic solutions were washed with 1M citric acid (2×37.5L) and water (2×37.5L). The organic layer was dried by concentration at reduced pressure and temperature at about 15° C.˜20° C. with concurrent addition of isopropylacetate (IPAC) to maintain the constant volume at about 100L. The solvent switch was completed when EA level was <5% by GC or HPLC analysis. The slurry was cooled to about 3° C. for an hour and then filtered. The cake was washed with IPAC (30L) and the solid was dried in air, which afforded about 84% isolated yield for the compound (8) (23.7 kg, 97 wt %).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]1[C@H:11]([CH3:12])[C@@H:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=2[I:23])[O:9][C:8]1=[O:24].[N+:34]([O-])([OH:36])=[O:35].O>CCOC(C)=O>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:30])([F:29])[F:31])[CH:27]=1)[CH2:6][N:7]1[C@H:11]([CH3:12])[C@@H:10]([C:13]2[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[C:15]([N+:34]([O-:36])=[O:35])[C:14]=2[I:23])[O:9][C:8]1=[O:24]
Reactant: O=[N+]([O-])O
Reactant: C[C@@H]1[C@@H](c2cc(C(F)(F)F)ccc2I)OC(=O)N1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H]1[C@@H](c2cc(C(F)(F)F)cc([N+](=O)[O-])c2I)OC(=O)N1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(4R,5R)-3-[3,5-Bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one was added in portions to 2 mL of fuming nitric acid at 0° C. The reaction mixture was stirred overnight at r.t., and then heated to 75° C. for 4 h. The reaction mixture was cooled and then added dropwise to a rapidly stirred mixture of 10 mL of water and 10 mL of EtOAc. The phases were separated and the organic phase was washed with 10 mL each of saturated NaHCO3 and brine, dried (Na2SO4), and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 CV of 5% EtOAc in hexanes followed by a linear gradient of 5→100% EtOAc in hexanes over 10 CV, to provide the title compound. Mass spectrum (ESI) 643 (M+1).
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C@@:5]([OH:11])([CH2:9][CH3:10])[C:6]([OH:8])=[O:7].[CH3:16]N(C=O)C.C1(C)C=CC=CC=1.[H-].[Na+]>O>[CH2:9]([C@@:5]1([C:6]([O:8][CH3:16])=[O:7])[CH2:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[O:11]1)[CH3:10]
Reactant: CC[C@](O)(Cc1ccccc1F)C(=O)O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC[C@@]1(C(=O)OC)Cc2ccccc2O1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
To a solution of the acid from step 1 (4.0 g, ca. 20 mmol) in 1:4 DMF:toluene (100 mL.) was added 60% NaH in mineral oil (1.76 g, 44 mmol) in 3 portions. The reaction mixture was stirred at 110° C. under N2 for 4 hrs. The reaction was cooled to room temperature and poured into cold water (100 mL). The aqueous layer was washed with hexane (50 mL), acidified with 2 N aqueous HCl and extracted with ethyl acetate (3×50 mL). The extracts were washed with brine (50 mL), dried and concentrated. The residue was dissolved in 7:1 benzene:MeOH (80 mL) and treated with TMSCHN2 (1M in hexane) until gas evolution ceased. The reaction was concentrated and the residue was chromatographed on silica gel eluting with 85:15 hexane:ethylacetate to give methyl (2S)-2-ethyl-2,3-dihydro-benzofuran-2-carboxylate.
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([O:20][CH3:21])=[O:19])=[C:13]([C:15](=[O:17])[NH2:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.[CH3:24][CH:25]([C:28]#[CH:29])[CH2:26]O.[OH2:30]>>[C:15]([C:13]1[N:14]=[C:7]2[C:6]3[CH:22]=[C:2]([C:29]#[C:28][C:25]([OH:30])([CH3:26])[CH3:24])[C:3]([F:23])=[CH:4][C:5]=3[O:11][CH2:10][CH2:9][N:8]2[C:12]=1[C:18]([O:20][CH3:21])=[O:19])(=[O:17])[NH2:16]
Reactant: C#CC(C)CO
Reactant: COC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Reactant: O
Product: COC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(C#CC(C)(C)O)cc1-2

Procedure:
Methyl 10-bromo-2-carbamoyl-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylate (2 g) was reacted with 2-Methyl-3-butyne-ol similar to as described in Procedure E to afford 2 g of methyl 2-carbamoyl-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylate following triteration from water. MS (Q1) 388 (M)+. Methyl 2-carbamoyl-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylate (1.5 g) was saponified with LiOH in water/THF to afford quantitative yield of 2-carbamoyl-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid. MS (Q1) 383 (M)+.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:21])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][C:15]=3[CH3:20])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Br:22][CH2:23][C:24]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[C:29]#[N:30])=[O:25]>CC(C)=O>[Br-:22].[C:1]12([CH2:11][NH:12][C:13]([C:14]3[C:15]([CH3:20])=[N+:16]([CH2:23][C:24]([C:26]4[CH:33]=[CH:32][CH:31]=[C:28]([C:29]#[N:30])[CH:27]=4)=[O:25])[CH:17]=[CH:18][CH:19]=3)=[O:21])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: Cc1ncccc1C(=O)NCC12CC3CC(CC(C3)C1)C2
Reactant: N#Cc1cccc(C(=O)CBr)c1
Solvent: CC(C)=O
Product: Cc1c(C(=O)NCC23CC4CC(CC(C4)C2)C3)ccc[n+]1CC(=O)c1cccc(C#N)c1
Product: [Br-]

Procedure:
A mixture of N-(adamantan-1-ylmethyl)-2-methylnicotinamide (300 mg, 1.05 mmol) and 3-(bromoacetyl)benzonitrile (235 mg, 1.05 mmol) in 10 mL of acetone is stirred at reflux for 2.5 days. After cooling to rt, most of the acetone is evaporated, and the remaining mixture is filtered. The collected solid is dried in vacuo to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.93 (1H, m), 8.86 (1H, bs), 8.62 (1H, d), 8.58 (1H, s), 8.33 (1H, d), 8.26 (1H, d), 8.14 (1H, t), 7.87 (1H, t), 6.60 (2H, s), 3.01 (2H, d), 2.67 (3H, s), 1.94 (3H, s), 1.63 (6H, m), 1.51 (6H, s).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:16][CH3:17])[CH2:3][O:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11]CC)=[O:10])=[CH:7][CH:6]=1.[OH-].[Na+].O.Cl>CCOCC.C(O)C>[CH3:1][C@@H:2]([CH2:16][CH3:17])[CH2:3][O:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1ccc(OC[C@@H](C)CC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CC[C@H](C)COc1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
A mixture of compound 8 (10.40 g, 0.04 mol), sodium hydroxide (11.67 g, 0.208 mol), water (23 ml) and ethanol (225 ml) was heated under reflux for 2 h. The solution was allowed to cool, to room temperature, and then acidified with dilute hydrochloric acid. The solvent was removed to leave a white solid which was dissolved in ether and washed successively with saturated sodium hydrogen carbonate solution (until no more effervescence was observed) and water. After drying the ether (MgSO4), the solvent was removed in vacuo and the white solid was recrystallised from ethanol to yield colourless crystals.
Reaction SMILES: I[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25](Br)[N:24]=1>[Li]CCCC.[Zn+2].[Br-].[Br-]>[Br:22][C:23]1[N:24]=[C:25]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:3]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(I)n2)cc1
Reactant: Brc1cccc(Br)n1
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Zn+2]
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)n3)n2)cc1

Procedure:
The title compound was prepared from 2-iodo-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example A.4) (0.900 g, 2.15 mmol), n-BuLi/ZnBr2 and commercially available 2,6-dibromopyridine (0.510 g, 2.15 mmol) according to Tetrahedron Letters 1996, 37(15), 2537 and the general procedure IVc protocol b. Obtained as a yellow oil (0.658 g, 60%, 88% purity). MS (ISP) 447.8 [(M+H)+] and 450.0 [(M+2+H)+].
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)=[CH:8]2)=[O:4].[NH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40].C[O-].[Na+]>>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:35])[C:5]([C:3]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[C:10]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3cccnc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cccnc2)c2c(cc(-c3cccnc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 33.4 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3,8-di-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (18 mg, 0.039 mmol), β-alanine (553 mg, 6.21 mmol) and NaOMe solution (9 mL, 4.66 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 6.8 mg of the title compound as a light yellow solid. MS: (+) m/z 522.29 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[C:19]3[N:21](C4CCCCO4)[N:22]=[C:23]([CH3:24])[C:18]3=[C:17]([C:31](=O)[CH3:32])[CH:16]=2)=[C:11]([F:34])[CH:10]=1)C1C=CC=CC=1.[CH3:35][C@H:36]1[CH2:41][NH:40][CH2:39][C@@H:38]([CH3:42])[N:37]1C(OC(C)(C)C)=O>>[CH3:35][C@@H:36]1[NH:37][C@H:38]([CH3:42])[CH2:39][N:40]([CH:31]([C:17]2[CH:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]=3[F:34])[N:20]=[C:19]3[NH:21][N:22]=[C:23]([CH3:24])[C:18]=23)[CH3:32])[CH2:41]1
Reactant: CC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2F)nc2c1c(C)nn2C1CCCCO1
Reactant: C[C@@H]1CNC[C@H](C)N1C(=O)OC(C)(C)C
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3F)cc(C(C)N3C[C@@H](C)N[C@@H](C)C3)c12

Procedure:
The title compound was prepared in analogy to Example 97 starting from 1-[6-(4-benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-ethanone and (2S,6R)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([F:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([F:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2ccc(F)cc2c1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc2ccc(F)cc2c1

Procedure:
A solution of 4-chloro-6-fluoro-quinoline-3-carboxylic acid ethyl ester (4.2 g, 16.6 mmol) and diisopropylethylamine (8.7 mL, 50 mmol) in ethanol (50 mL) was hydrogenated over 10% palladium on carbon (0.2 g) at 1 atmosphere of hydrogen for 1 day. Additional catalyst (0.3 g) was added and the hydrogenation was continued at 50 psi of hydrogen for 2 hours. The catalyst was removed by filtration. The solvent was evaporated in vacuo, and the residue was partitioned between water and dichloromethane. The organic layer was dried over sodium sulfate. The product was preabsorbed onto silica gel and purified by flash chromatography, using a gradient of ethyl acetate (0% to 30%) in heptanes as the eluant, to give the product as a yellow solid, 2.2 g (60%). MS: m/z 219.9 (MH+).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][CH:15]=2)[CH2:5][CH2:4]1.C(O)(=O)C.C(N(CC)CC)C.[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][C:33]=1[O:40][CH2:41][CH3:42].C([BH3-])#N.[Na+]>C(O)C>[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][N:3]2[CH2:4][CH2:5][CH:6]([NH:9][C:10]3[CH:11]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][CH:15]=3)[CH2:7][CH2:8]2)=[CH:34][C:33]=1[O:40][CH2:41][CH3:42]
Reactant: CCOc1cc(C=O)ccc1Cl
Reactant: CC(=O)Nc1cccc(NC2CCNCC2)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOc1cc(CN2CCC(Nc3cccc(NC(C)=O)c3)CC2)ccc1Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 12.4 %

Procedure:
To a solution of N-[3-(piperidin-4-ylamino)-phenyl]-acetamide dihydrochloride (61.2 mg, 0.2 mmol, 1.0 equiv; intermediate B1), acetic acid (60.1 mg, 1.0 mmol, 5.0 equiv) and triethylamine (40.5 mg, 0.4 mmol, 2.0 equiv) in ethanol (1 mL) was added 4-chloro-3-ethoxy-benzaldehyde (46.1 mg, 0.25 mmol, 1.25 equiv; intermediate E2, vide infra) and the mixture stirred at 50° C. After 1 h, sodium cyanoborohydride (15.1 mg, 0.24 mmol, 1.2 equiv), dissolved in ethanol (1 mL), was added and the mixture stirred at 50° C. over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 10.0 mg (12%) of the title compound. MS (ISP): 402.3 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][OH:21])[C:13](=[O:22])[NH:12][C:11]=2[N:10]=[C:9]1[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:36][CH3:37].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][OH:21])[C:13](=[O:22])[N:12]([CH2:36][CH3:37])[C:11]=2[N:10]=[C:9]1[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:33])([F:32])[F:34])[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2nc(Oc3cccc(OC(F)(F)F)c3)n(Cc3ccccc3)c2c(=O)n1CCCO
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(CCCO)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
To a solution of 7-benzyl-1-(3-hydroxypropyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (1.2 g, 2.52 mmol, example 59) in DMF (5 mL) was added iodoethane (0.7 g, 4.49 mmol), followed by potassium carbonate (0.7 g, 5.07 mmol). The reaction was stirred at 80° C. for 2 h; then it was cooled and partitioned between ethyl acetate and water. The phases were separated and the organic phase was washed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated to give 7-benzyl-3-ethyl-1-(3-hydroxypropyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (0.62 g, 49.2% yield) as yellow solid.
Reaction SMILES: CC(=O)CC(=O)C.O.[OH-].[Ba+2:10].[OH-].C(O)CCC.[C:17]([OH:21])(=[O:20])[CH2:18][CH3:19]>CCCCO.CCCCO.CCCCO.CCCCO.[Ti]>[C:17]([O-:21])(=[O:20])[CH2:18][CH3:19].[Ba+2:10].[C:17]([O-:21])(=[O:20])[CH2:18][CH3:19]
Reactant: CCC(=O)O
Agent: [Ti]
Agent: [Ba+2]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Solvent: CC(=O)CC(C)=O
Product: CCC(=O)[O-]
Reaction time: 12 h

Procedure:
2,4 pentanedione (Acac) is degassed by a freeze/pump/thaw method on a Schlenk line over a bed of grade 4A molecular sieves and back filled with argon gas. In a nitrogen-filled drybox, 34.041 g of titanium(IV) n-butoxide (Acros; 0.100 moles) are placed into a 100 ml bottle, and 20.020 g of 2,4 pentanedione (0.200 moles; Aldrich) is then added dropwise and left to stir for 12 hours. In a fumehood, 31.750 g of barium hydroxide hydrate (0.101 moles; Aldrich) is added to a 500 ml volumetric flask. 200 ml of a 50:50 solution of 1-butanol/propanoic acid would then be added and stirred to form barium propanoate. The titanium solution [bis(acetylacetonato)/bis(butoxo) titanium] is then removed from the drybox and added to the volumetric flask containing the barium hydroxide solution. The round bottom flask is rinsed several times with 50:50 1-butanol:propanoic acid solution into the volumetric flask. A 50:50 1-butanol:propanoic acid solution is then added to the 500 ml flask up to the mark, and a stir bar is then added. The solution is stirred for an additional 12 hours.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][C:13]#[N:14].C1CCCCC1.Br.C(N)C1C=CC=CC=1>C(OCC)C>[CH2:1]([NH:8][CH2:10][CH2:11][CH2:12][C:13]#[N:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: N#CCCCBr
Agent: Br
Solvent: C1CCCCC1
Solvent: CCOCC
Product: N#CCCCNCc1ccccc1
Yield: 66 %

Procedure:
32.2 g of benzylamine, 14.8 g of 4-bromobutyronitrile and 30 ml of cyclohexane are stirred at room temperature for 12 hours. After the addition of diethyl ether the separated benzylamine hydrobromide is filtered off; the ether phase is washed with water, dried and concentrated by evaporation. The residue is distilled in vacuo to yield 11.5 g (66% of theory) of 4-benzylaminobutyronitrile (B.P. 114° to 120°/0.05 mm Hg).
Reaction SMILES: O=[C:2]1[CH:6]([C:7]([O:9][CH3:10])=[O:8])[CH2:5][S:4][CH2:3]1.[CH:11]1([NH:17][C:18]([NH2:20])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C(C)=CC=CC=1>O>[CH:11]1([NH:17][C:18]([NH:20][C:2]2[CH2:3][S:4][CH2:5][C:6]=2[C:7]([O:9][CH3:10])=[O:8])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)C1CSCC1=O
Reactant: NC(=O)NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: COC(=O)C1=C(NC(=O)NC2CCCCC2)CSC1

Procedure:
15.1 parts by weight of methyl 3-keto-1,5-dihydrothiophene-4-carboxylate, 14.2 parts by weight of cyclohexylurea and 0.5 part by weight of p-toluenesulfonic acid in 100 parts by weight of xylene were refluxed for 4 hours in an apparatus equipped with a water separator. The mixture was cooled, and the residue was then filtered off under suction and recrystallized from toluene. 20.3 parts by weight of N-cyclohexyl-N'-(3-methoxycarbonyl-2,5-dihydrothien-4-yl)-urea of melting point 154°-155° C. were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:30][CH2:31][CH3:32])[C:28]=1[F:29])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([OH:24])[CH:17]=2)[CH2:10][CH2:9]1)[CH3:2].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:31]([O:30][C:27]1[CH:26]=[C:6]([CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:28]=1[F:29])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:16]2[CH:17]=[C:18]([O:24][S:34]([CH3:33])(=[O:36])=[O:35])[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=2)=[O:25])[CH2:10][CH2:9]1)[CH3:32]
Reactant: CS(=O)(=O)Cl
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cc(O)cc(OC)c3)CC2)cc(OCC)c1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OS(C)(=O)=O)c3)CC2)cc(OCC)c1F

Procedure:
In analogy to the procedure described in example 72a), N-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-3-hydroxy-5-methoxy-benzamide (example 257) was reacted with methanesulfonyl chloride, N-ethyl-diisopropylamine in CH2Cl2 at rt to yield the title compound as colorless solid. MS: 525.2 (MH+).
Reaction SMILES: [CH2:1]([I:4])[CH2:2][CH3:3].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14]>CC(=O)C(C)(C)C>[I-:4].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:16]2[CH:21]=[CH:20][N+:19]([CH2:1][CH2:2][CH3:3])=[CH:18][CH:17]=2)[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14]
Reactant: COc1cc(-c2ccncc2)ccc1[N+](=O)[O-]
Reactant: CCCI
Solvent: CC(=O)C(C)(C)C
Product: CCC[n+]1ccc(-c2ccc([N+](=O)[O-])c(OC)c2)cc1
Product: [I-]
Temperature: 100 °C

Procedure:
n-Propyliodide (200 mL, 2.05 mol) was added to a solution of 4-(3-methoxy-4-nitrophenyl)pyridine (25.0 g, 109 mmol) in pinacolone (500 mL). The reaction was fitted with a reflux condenser, stirred, and heated at 100° C. for 12 h. A light brown suspension was observed. An aliquot (˜2.0 mL) was taken out from the reaction mixture, concentrated, and analyzed by 1H NMR which revealed the formation of the alkylated product and the absence of starting material. The reaction was cooled; the solids were filtered off and rinsed once with cold (0° C.) acetone to afford 4-(3-methoxy-4-nitrophenyl)-1-propylpyridinium iodide as a light brown residue (29.0 g, 67% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.3 Hz, 3 H), 1.99 (dt, J=7.3, 7.3 Hz, 2 H), 4.08 (s, 3 H), 4.59 (t, J=7.1 Hz, 2 H), 7.78 (dd, J=1.5, 8.4 Hz, 1H), 7.92 (d, J=1.5 Hz, 1 H), 8.13 (d, J=8.4 Hz, 1 H), 8.65 (d, J=7.0 Hz, 2 H), 9.22 (d, J=6.6 Hz, 2 H).